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TYROSINE KINASE INHIBITORS

by Selleckchem | Apr 19 2012

TYROSINE KINASE INHIBITORS
Amongst a diversified world of signal transduction proteins, Tyrosine kinase proteins are important due to their role in different processes like activation or inhibition of expression of genes involved in growth, cell division, differentiation and cell death. Aberrations in any of such tyrosine kinases may lead to disruption in any of the above mentioned function and may develop tumor. In any type of cancer where any of the cell cycle regulatory protein that is affected by tyrosine kinases is disturbed, inhibition of Tyrosine kinases may work well to cope with the condition. They are attractive targets for anti-cancer drugs as they are the ones that start the activity. TKIs (Tyrosine Kinase Inhibitors) may affect different types of Tyrosine kinases, therefore are called as multikinase inhibitors they may be receptor or non-receptor tyrosine kinases. If we know the type of kinase involved in the cancerous condition, e.g., if VEGF involved in breast cancer, the drug of choice is definitely a TKI [1]. Tyrosine Inhibitors show promising results when used for (GISTs) gastrointestinal stromal tumors [2] and for solid tumors [3]. For (ALL) acute lymphoblastic leukemia, FLT3 TKI are being used for treatment [4].

SUNITINIB AND ITS PROPERTIES
Sunitinib is one of the examples of Tyrosine kinase inhibitors and Sunitinib PDGFR inhibitor and Sunitinb VEGFR inhibitor are its further examples. Sunitinib structure has carboxamide group in it and it is being used quite efficaciously nowadays. Sunitinib IC50 for VEGFR1, 2, and 3 is 2, 9 and 17 nM and for c-Kit and PDGF-R it is 4 and 8 nM respectively. One can buy Sunitinib 1 gm in $80. Sunitinib solubility is 40 mg/ml for DMSO but poor for water and ethanol. Sunitinib stability can be maintained for upto 2 years if stored at -20oC.
A huge amount of data is available on preclinical research on Sunitinib to prove it as a strong anti-tumor and anti-angiogenic compound [5]. The pharmacokinetics of the drug and safety profile has been studied for humans too [6]. The studies favor its use in cancer patients successfully [7] as Sunitinib c-Kit inhibitor [8]. Use of this drug as anti-angiogenic inhibitor has been encouraged by studies on it as Sunitinib VEGFR inhibitor and as Sunitinib PDGFR inhibitor [9]. Sunitinib has been studied as FLT3 inhibitor in the patients of (NSCLC) non small cell lung cancer [10]. Sunitinib has been studied in clinical trial phase III as VEGF Tyrosine Kinase Inhibitor [11] ALL TKI and [12] andFLT3 TKI [13]. Sunitinib has shown quite efficacious results against (RCC) renal carcinoma cancer [14] and different types of hematologic malignant tumors in humans [15].

CLINICAL TRIALS
Sunitinib clinical trials done on patients with different types of cancerous conditions have shown encouraging results. Mode of action of the drug was clearly understood in clinical trial phase I [16]. In most of the diseases Sunitinib is in clinical trial phase II e.g., In NSCLC (Non-small cell lung cancer) patients [17] and patients with lung cancer in advanced stages [18], colorectal cancer [19], B cell lymphoma [20], breast cancer [21] and in patients of ovarian carcinoma [22]. Combinatorial treatment of Sunitinib with Docetaxel and Prednisone has also been studied on the patients of prostate cancer and has yielded remarkable results in clinical trials phase I/II [23]. The safety and efficacy of the drug has been studied GISTs patients [24] and has been successfully studied in phase III for the same disease [25]. Sunitinib has also been studied in phase III clinical trials in patients of renal cell carcinoma (RCC) [26] and tumors of pancreatic neuroendocrine [27].

REFERENCES:
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2. George, S., Sunitinib, a multitargeted tyrosine kinase inhibitor, in the management of gastrointestinal stromal tumor. Curr Oncol Rep., 2007.
3. Steeghs, N.e.a., Small Molecule Tyrosine Kinase Inhibitors in the Treatment of Solid Tumors: An Update of Recent Developments. Annals of Surgical Oncology, 2006.
4. Illmer, T.e.a., FLT3 Kinase Inhibitors in the Management of Acute Myeloid Leukemia. Clinical Lymphoma, Myeloma & Leukemia, 2007.
5. Christensen, J.G., A preclinical review of sunitinib, a multitargeted receptor tyrosine kinase inhibitor with anti-angiogenic and antitumour activities. Annals of Oncology, 2007.
6. Faivre, S.e.a., Safety, Pharmacokinetic, and Antitumor Activity of SU11248, a Novel Oral Multitarget Tyrosine Kinase Inhibitor, in Patients With Cancer. Journal of Clinical Oncology, 2006.
7. Abrams, T.J.e.a., SU11248 Inhibits KIT and Platelet-derived Growth Factor Receptor β in Preclinical Models of Human Small Cell Lung Cancer. Mol. Cancer Ther., 2003.
8. Hartmann, J.T.a.K., L., Sunitinib and periodic hair depigmentation due to temporary c-KIT inhibition. Arch Dermatol., 2008.
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11. Jain, R.K.e.a., Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nature Clinical Practice Oncology, 2006.
12. Stam, R.W.a.P., R., FLT3 Inhibitors as Therapeutic Agents in MLL Rearranged Acute Lymphoblastic Leukemia. New Agents for the Treatment of Acute Lymphoblastic Leukemia, 2011.
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17. Novello, S.e.a., Phase II study of continuous daily sunitinib dosing in patients with previously treated advanced non-small cell lung cancer. British Journal of Cancer, 2009.
18. Schneider, B.J.e.a., Phase II Trial of Sunitinib Maintenance Therapy After Platinum-Based Chemotherapy in Patients with Extensive-Stage Small Cell Lung Cancer. Journal of Thoracic Oncology, 2011.
19. Saltz, L.B.e.a., Phase II Trial of Sunitinib in Patients With Metastatic Colorectal Cancer After Failure of Standard Therapy. Journal of Clinical Oncology, 2007.
20. Buckstein, R.e.a., Sunitinib in relapsed or refractory diffuse large B-cell lymphoma: a clinical and pharmacodynamic phase II multicenter study of the NCIC Clinical Trials Group. Leukemia & Lymphoma, 2011.
21. Burstein, H.J.e.a., Phase II Study of Sunitinib Malate, an Oral Multitargeted Tyrosine Kinase Inhibitor, in Patients With Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane. Journal of Clinical Oncology, 2008.
22. al, B.J.J.e., A phase II study of sunitinib in patients with recurrent epithelial ovarian and primary peritoneal carcinoma: an NCIC Clinical Trials Group Study. Annals of Oncology, 2011.
23. Zurita, A.J.e.a., Sunitinib in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic, castration-resistant prostate cancer: a phase 1/2 clinical trial. Annals of Oncology, 2011.
24. Demetri, G.D.e.a., Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. The Lancet, 2006.
25. Marx, J.e.a., Encouraging results for second-generation antiangiogenesis drugs. Science, 2005.
26. Eichelberg, C.e.a., Sequential Use of the Tyrosine Kinase Inhibitors Sorafenib and Sunitinib in Metastatic Renal Cell Carcinoma: A Retrospective Outcome Analysis. European Urology, 2008.
27. Raymond, R.e.a., Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors. N Engl J Med, 2011.